Field of the Invention
The present invention is directed to prodrugs of proton pump inhibitors which are useful as anti-ulcer agents. More particularly, the present invention is directed to prodrugs that slowly hydrolyze to provide benzimidazole-type proton pump inhibitors which inhibit exogenously or endogenously gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases in mammals, including humans.
Brief Description of the Prior Art
Benzimidazole derivatives intended for inhibiting gastric acid secretion are disclosed in the U.S. Pat. Nos. 4,045,563; 4,255,431; 4,628,098; 4,686,230; 4,758,579; 4,965,269; 5,021,433; 5,430,042 and 5,708,017. Generally speaking, the benzimidazole-type inhibitors of gastric acid secretion work by undergoing a rearrangement to form a thiophilic species which then covalently binds to gastric H,K-ATPase, the enzyme involved in the final step of proton production in the parietal cells, and thereby inhibits the enzyme. Compounds which inhibit the gastric H,K-ATPase enzyme are generally known in the field as xe2x80x9cproton pump inhibitorsxe2x80x9d (PPI).
Some of the benzimidazole compounds capable of inhibiting the gastric H,K-ATPase enzyme have found substantial use as drugs in human medicine and are known under such names as LANSOPRAZOLE (U.S. Pat. No. 4,628,098), OMEPRAZOLE (U.S. Pat. Nos. 4,255,431 and 5,693,818), PANTOPRAZOLE (U.S. Pat. No. 4,758,579), and RABEPRAZOLE (U.S. Pat. No.5,045,552). The diseases treated by proton pump inhibitors and specifically by the four above-mentioned drugs include peptic ulcer, heart burn, reflux esophagitis errosive esophagitis, non-ulcer dispepsia, infection by Helicobacter pylori, alrynitis and asthma among others.
Whereas the proton pump inhibitor type drugs represent substantial advance in the field of human and veterinary medicine, they are not totally without shortcomings or disadvantages. The shortcomings of the presently used proton pump inhibitor (PPI) type drugs can be best explained by a more detailed description of the mode of their action, the diseases or condition against which they are employed and the circumstances of their application. Thus, acid related diseases include but are not limited to erosive esophagitis, esophageal reflux, gastric and duodenal ulcer, non-ulcer dyspepsia and infection by Helicobacter pylori. Current therapy of all but the infection by H. pylori bacteria involves treatment with drugs designed to suppress acid secretion, one type of which are the above-mentioned proton pump inhibitors.
The presently used proton pump inhibitors are pyridyl methyl sulfinyl benzimidazoles (or compounds of closely related structure) with a pKa of 4.0 to 5.0. Their mechanism of action requires accumulation in the acidic space of the parietal cell (secretory canaliculus, pH ca. 1.0) and subsequently hydrogen ion catalyzed conversion to the reactive thiophilic species that is capable of inhibiting the gastric ATPase, enzyme resulting in effective inhibition of gastric secretion. Because of this mechanism the presently used PPI type drugs require specialized gastro protection to remain active for duodenal absorption. For this reason, and due to sensitivity to degradation in the acid milieu of the stomach, oral formulations of the PPI drugs are usually enteric coated. The need for enteric coating is a shortcoming because enteric coating is expensive and moisture sensitive.
Because of the requirement for accumulation in the acid space of the parietal cell, acid secretion is necessary for the efficacy of the PPI type drugs. It was found that the plasma half life of these drugs is between 60 to 90 minutes. All acid pumps are not active at any one time, rather only about 75% are active on the average during the time the drug is present in the blood following oral administration. It was also found in medical experience that on a currently used once-a-day oral administration therapy the maximal inhibition of stimulated acid output is approximately 66%. This is due to a combination of the short plasma half life of the drug, to the limited number of acid pumps active during presentation of the drug and to the turn-over of acid pumps. In present practice it is not possible to control night time acid secretion by evening therapy of oral administration because the drug is dissipated from the plasma by the time acid secretion is established after midnight. The ideal target for healing in acid related diseases and for treatment of H. pylori infection (in conjunction with antibiotics), as well as for relief of symptoms of non-ulcer dyspepsia would be full inhibition of acid secretion. With the currently used PPI type drugs this is achieved only by intravenous infusion; in case of the drug OMEPRAZOLE this requires intravenous infusion of 8 mg per hour. Clearly, there is a need in the art for a drug or drugs acting through the mechanism of PPI-type drugs which can attain or approach full inhibition of acid secretion through oral therapy.
Because of the less than full inhibition of acid secretion and less than 24 hour inhibition through oral administration that is attained by the current dosage forms of currently used PPI-type drugs, therapy for healing of gastric and duodenal ulcerations is 4 to 8 weeks. This is in spite of the fact that the generation time of surface cells of the esophagus, stomach and duodenum is approximately 72 hours. Undoubtedly the presently observed prolonged healing times with these drugs is due to inadequate acid suppression and acid related damage. The foregoing underscores the need in the art for a drug or drugs acting through the mechanism of PPI-type drugs which can attain or approach full inhibition of acid secretion through oral therapy.
As further pertinent background to the present invention, applicants note the concept of prodrugs which is well known in the art. Generally speaking, prodrugs are derivatives of per se drugs, which after administration undergo conversion to the physiologically active species. The conversion may be spontaneous, such as hydrolysis in the physiological environment, or may be enzyme catalyzed. From among the voluminous scientific literature devoted to prodrugs in general, the foregoing examples are cited: Design of Prodrugs (Bundgaard H. ed.) 1985 Elsevier Science Publishers B. V. (Biomedical Division), Chapter 1; Design of Prodrugs: Bioreversible derivatives for various functional groups and chemical entities (Hans Bundgaard); Bundgaard et al. Int. J. of Pharmaceutics 22 (1984) 45-56 (Elsevier); Bundgaard et al. Int. J. of Pharmaceutics 29 (1986) 19-28 (Elsevier); Bundgaard et al. J. Med. Chem. 32 (1989) 2503-2507 Chem. Abstracts 93, 137935y (Bundgaard et al.); Chem. Abstracts 95, 138493f (Bundgaard et al.); Chem. Abstracts 95, 138592n (Bundgaard et al.); Chem. Abstracts 110, 57664p (Alminger et al.); Chem. Abstracts 115, 64029s (Buur et al.); Chem. Abstracts 115, 189582y (Hansen et al.); Chem. Abstracts 117, 14347q (Bundgaard et al.); Chem. Abstracts 117, 55790x (Jensen et al.); and Chem. Abstracts 123, 17593b (Thomsen et al.).
As far as the present inventors are aware, there are no prodrugs of the proton pump inhibitors presently in use. However, several U.S. patents describe compounds which can act as prodrugs of certain proton pump inhibitors. Specifically, U.S. Pat. No. 4,686,230 (Rainer et al.) describes derivatives of pyridyl methyl sulfinyl benzimidazoles which include a group designated xe2x80x9cR5xe2x80x9d on one of the benzimidazole nitrogens. The xe2x80x9cR5xe2x80x9d group is expected to cleave under physiological condition, or under the influence of an enzyme to provide the corresponding compound with a free N-H bond (see column 3 of U.S. Pat. No. 4,686,230). U.S. Pat. Nos. 5,021,433 (Alminger et al.), 4,045,563 (Berntsson et al.), 4,965,269 and (Brxc3xa4ndstrxc3x6m et al.) also describe pyridyl methyl sulfinyl benzimidazoles where one of the nitrogens of the benzimidazole moiety bears a substituent that cleaves under physiological or enzymatic conditions. U.S. Pat. No. 4,045,563 (Berntsson et al.)describes N-alkoxycarbonyl benzimidazole derivates.
A publication by Sih., et al. Journal of Medicinal Chemistry, 1991, vol. 34, pp 1049-1062, describes N-acyloxyalkyl, N-alkoxycarbonyl, N-(aminoethyl), and N-alkoxyalkyl derivatives of benzimidazole sulfoxide as prodrugs of proton-pump inhibitors. According to this article these prodrugs exhibited improved chemical stability in the solid state and in aqueous solutions, but had similar activity or less activity than the corresponding parent compounds having a free imidazole N-H group. This publication does not provide data regarding the duration of the inhibitory activity of these prodrugs.
The present invention represents further advance in the art in that it provides prodrugs of improved structure of the proton pump inhibitor type drugs and provides proof of the suitability of the prodrugs of the invention for use as prodrug of proton pump inhibitors, with improved efficacy in therapy of acid related diseases due to prolongation of the presence of the proton pump inhibitors in the body.
The present invention relates to compounds of Formula 1
Het1xe2x80x94Xxe2x80x94S(O)xe2x80x94Het2
wherein
Het1 is selected from the formulas shown below 
X is selected from the formulas 
and Het2 is selected from the formulas 
where N in the benzimidazole moiety means that one of the ring carbons may be exchanged for an unsubstituted N atom;
R1, R2 and R3 are independently selected from hydrogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 10 carbons, alkoxy of 1 to 10 carbons, fluoro substituted alkoxy of 1 to 10 carbons, alkylthio of 1 to 10 carbons, fluoro substituted alkylthio of 1 to 10 carbons, alkoxyalkoxy of 2 to 10 carbons, amino, alkylamino and dialkylamino each of the alkyl groups in said alkylamino and dialkyl amino groups having 1 to 10 carbons, halogen, phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, phenylalkoxy, each of the alkyl groups in said alkyl substituted phenyl, alkoxy substituted phenyl and phenylalkoxy having 1 to 10 carbons, piperidino, morpholino or two of the R1, R2 and R3 groups jointly forming a 5 or 6 membered ring having 0 or 1 heteroatom selected from N, S and O;
R4 and R5 are independently selected from hydrogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 10 carbons, phenylalkyl, naphthylalkyl and heteroarylalkyl, alkyl in said phenylalkyl, naphthylalkyl and heteroarylalkyl groups having 1 to 10 carbons;
R6 is hydrogen, halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 10 carbons, alkoxy having 1 to 10 carbons or fluoro substituted alkoxy having 1 to 10 carbons;
R6 through R9 are independently selected from hydrogen, halogen, alkyl of 1 to 10 carbons, halogen substituted alkyl of 1 to 10 carbons, alkoxy of 1 to 10 carbons, halogen substituted alkoxy of 1 to 10 carbons, alkylcarbonyl, alkoxycarbonyl the alkyl group in said alkylcarbonyl and alkoxycarbonyl having 1 to 10 carbons, oxazolyl, imidazolyl, thiazolyl, morpholinyl, piperazinyl, pyrazinyl, pyrazolyl, or any two adjacent ones of the R6 through R9 groups may form a ring that may optionally include a heteroatom selected from N, O and S and said ring may be further substituted;
R10 is hydrogen, alkyl of 1 to 10 carbons, or R10 may form an alkylene chain together with R3,
R11 and R12 are independently selected from hydrogen, halogen, alkyl of 1 to 10 carbons and halogen substituted alkyl of 1 to 10 carbons;
R15 has the formula below 
where
R17 is alkyl of 1 to 10 carbons, halogen substituted alkyl of 1 to 10 carbons, alkoxy having 1 to 10 carbons, halogen substituted alkoxy of 1 to 10 carbons, alkylthio having 1 to 10 carbons, halogen substituted alkylthio of 1 to 10 carbons, alkoxy carbonyl having 1 to 10 carbons, halogen substituted alkoxy carbonyl having 1 to 10 carbons, F, Cl, Br, I, NO2 , CN, OCOalkyl, NH2, alkylamino and dialkylamino where in said OCOalkyl, alkylamino and dialkylamino groups each of said alkyl group has 1 to 10 carbons, further R17 is carbamoyl, N- lower alkyl carbamoyl having 1 to 6 carbons, alkylcarbonyl having 1 to 10 carbons, (alkoxycarbonyl)alkoxy groups of each of said alkoxy group has 1 to 10 carbons, (alkoxycarbonyl)alkyl groups of each of said alkoxy or alkyl group has 1 to 10 carbons, (carbamoyl)alkoxy having 1 to 10 carbons, (N-alkylcarbamoyl)alkoxy where each of said alkoxy or alkyl groups has 1 to 6 carbons, (N,N-dialkylcarbamoyl)alkoxy where each of said alkoxy or alkyl groups has 1 to 6 carbons, (N-alkyl substituted or unsubstituted carbamoyl)poly(alkoxy)n where each of said alkoxy or alkyl groups has 1 to 6 carbons and where n represents an integer selected from 2 to 5, (N-alkyl substituted or unsubstituted carbamoyl)alkyl where each of said alkyl groups has 1 to 5 carbons, (carbamoyl)alkenyl having 2 to 5 carbons, (dialkylcarbamoyl)alkenyl where each of said alkyl groups has 1 to 5 carbons and where the alkenyl group has 2 to 5 carbons, [N-(heteroaryl)carbamoyl]alkyl having 1 to 10 carbons wherein heteroaryl has 1 to 3 heteroatoms independently selected from N, O, and S, [N-(heteroaryl)carbamoyl]alkoxy having 1 to 10 carbons wherein heteroaryl has 1 to 3 heteroatoms independently selected from N, O, and S, poly(alkoxy)n where each of said alkoxy groups has 2 to 10 carbons and wherein n represents an integer selected from 2 to 5, 2-[(2-oxy-ethoxy)-ethoxyl-(ethoxy)n-ethanoxy wherein n represents an integer selected from 1 to 3, guanidinyl group, ureido group, (dialkylamino)alkyl where each of said alkyl groups has 1 to 5 carbons, (dialkylamino)alkoxy where each of said alkyl or alkoxy groups has 1 to 5 carbons, dialkylamino-poly(alkoxy)n where each of said alkyl or alkoxy groups has 1 to 5 carbons and wherein n represents an integer selected from 2 to 5, [N-(carbamoylalkyl)carbamoyl]alkoxy where each of said alkoxy or alkyl groups has 1 to 5 carbons, (N-peptidyl carbamoyl)alkoxy where the alkoxy group has 1 to 5 carbons and wherein said peptidyl consists of two or three amino acids, N-peptidyl amido wherein said peptidyl consists of two or three amino acids, [N-(carbamoylalkyl)carbamoyl]alkyl where each of said alkyl groups has 1 to 5 carbons, [N-[(dicarbamoyl)alkyl]carbamoyl]alkoxy where each of said alkoxy or alkyl groups has 1 to 5 carbons, [N-(di(alkoxycarbonyl)alkyl]carbamoyl]alkoxy where each of said alkoxy or alkyl groups has 1 to 5 carbons, [N-[(dicarbamoyl)alkyl]amido where alkyl groups has 1 to 5 carbons, [N-[di(alkoxycarbonyl)alkyl]amido where each of said alkoxy or alkyl groups has 1 to 5 carbons, [N-[(carbamoyl)alkyl]amido where alkyl groups has 1 to 5 carbons, [N-[(alkoxycarbonyl)alkyl]amido where each of said alkoxy or alkyl groups has 1 to 5 carbons, [N-[[N-(heteroaryl) carbamoyl]alkyl]carbamoyl]alkoxy where each of said alkoxy or alkyl groups has 1 to 5 carbons and wherein said heteroaryl has 1 to 3 heteroatoms independently selected from N, O, and S, [(tri-alkyl)ammonium]-alkoxy where each of said alkoxy or alkyl groups has 1 to 5 carbons, SO3xe2x88x92, aminosulfonyl, (sulfonato)alkyl having 2 to 5 carbons, (sulfonato)alkoxy having 2 to 5 carbons, N-[(sulfonato)alkyl]amido having 2 to 5 carbons, maleimido- and succinimido, and
R21 is (aryl)alkyl, (heteroaryl)alkyl where alkyl has 1 to 10 carbons, phenyl, naphthyl or heteroaryl having 1 to 3 heteroatoms independently selected from N, O and S, said phenyl, naphthyl or heteroaryl groups being unsubstituted or substituted with 1 to 5 R17 groups,
or to a pharmaceutically acceptable salt of said compounds.
The compounds of the invention are sulfoxides and have an asymmetric center in the sulfur atom. Both the pure enatiomers, racemic mixtures and unequal mixtures of the two are within the scope of the present invention. Some of the compounds of the invention may have one or more asymmetric carbon atoms (for example in a branch-chained alkyl group). All optical isomers, racemates, diastereomers and their mixtures are within the scope of the invention.
The compounds of the invention act as prodrugs of proton pump inhibitor type drugs which are useful for inhibiting gastric acid secretion. The compounds of the invention have excellent stability in tablet or capsule form, are acid stable, have excellent bioavailability and plasma half life which is significantly longer than the plasma half life of the presently used proton pump inhibitors.
The chemical structure of the compounds of the invention is shown and described in broad terms in the Summary of the Invention in connection with Formula 1. As it can be seen in the formula, the compounds of the invention are pyridyl methyl sulfinyl benzimidazoles, or compounds of closely related structure, wherein one of the benzimidazole nitrogens is substituted with a group (designated R15 in Formula 1) that gradually cleaves under physiological conditions and thereby provides the pyridyl methyl sulfinyl benzimidazole compound (or compound of closely related structure) which has a free N-H function in the benzimidazole (or related) moiety. The compound thus obtained by cleavage of the R15 group then undergoes the acid catalyzed rearrangement and provides the thiophilic species which inhibits the H,K-ATPase enzyme involved in gastric acid production. Thus, the novel compounds of the present invention bearing the R15 group are prodrugs of the proton pump inhibitor compounds which could also be depicted by Formula 1, where, however the R15 group would be designated hydrogen.
Generally speaking, among the prodrugs compounds of the present invention those are preferred wherein the structure of the pyridyl methyl sulfinyl benzimidazole or structurally related moiety is also preferred in the prior art. In other words, preferably prodrugs are provided in accordance with the present invention for those proton pump inhibitor drugs which are themselves preferred.
Referring now to the specific designation of symbols in connection with Formula 1, compounds are preferred in accordance with the present invention wherein the moiety designated Het1 is pyridyl substituted with alkyl, O-alkyl, O-alkoxyalkyl and/or O-fluoroalkyl groups. Most preferred substituents for the pyridine moiety, designated R1, R2 and R3 in Formula 1, are CH3Oxe2x80x94, CH3xe2x80x94, CF3CH2Oxe2x80x94, and CH3O(CH2)3Oxe2x80x94.
The moiety designated X in Formula 1 is preferably a methylene (xe2x80x94CH2xe2x80x94) group, or a xe2x80x94CHR10 group and the methylene or xe2x80x94CHR10 group is preferably attached in xcex1 position to the nitrogen in the pyridine moiety. Compounds where the X is ortho phenylene or substituted ortho phenylene are also preferred; in the most preferred compounds X is methylene.
Referring now to the group designated Het2 in Formula 1, this moiety is preferably a substituted benzimidazole. The R6 through R9 groups preferably are selected from hydrogen, chlorine and fluoro-substituted alkoxy groups, with hydrogen, chlorine, CF2HOxe2x80x94 and CH3Oxe2x80x94 being even more preferred.
Referring now to the group designated R15 in connection with Formula 1 it will be apparent to those skilled in the art that this group represents the principal novel structural feature of the present invention. Among the R15 groups shown in connection with Formula 1 the phenylsulfonyl and heteroarylsulfonyl groups (designated R21(R17)SO2xe2x80x94) are preferred. Even more preferably the aryl portion (R21) is phenyl or pyridyl unsubstituted or substituted with 1 to 3 R17 groups. When the R21 group is substituted, then the substituent (R17) is preferably selected from Cl, Br, F, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, di-(alkyl)amino, alkoxycarbonyl, (alkoxycarbonyl)alkoxy, ureido, guanidinyl, carbamoyl, N-alkyl carbamoyl, carbamoylalkyl, (N-alkyl carbamoyl)alkyl, (carbamoyl)alkenyl, (dialkylcarbamoyl)alkenyl, di-(alkylamino)alkoxy, morpholinyl, (morpholin-4-yl)alkoxy, (morpholin-4-yl)poly(alkoxy)n where n is an integer having the value of 2 to 5, di-(alkylamino)alkyl, poly(alkoxy)n alkoxy where n is an integer having the value of 1 to 5, 2-[(2-oxy-ethoxy)-ethoxy]-(ethoxy)n-ethanoxy wherein n represents an integer selected from 1 to 3, (carbamoyl)alkoxy, [(N-(alkyl)carbamoyl]alkoxy, [N,N-(dialkyl)carbamoyl)alkoxy, (N,N-dialkylcarbamoyl)alkyl, [N-(heteroaryl)carbamoyl]alkyl, [N-(heteroaryl)carbamoyl]alkoxy, [N-(aryl)carbamoyl]alkoxy, [N-[(dicarbamoyl)alkyl]carbamoyl]alkoxy, [N-[(carbamoyl)alkyl]carbamoyl]alkoxy, [N-[(N-alkyl carbamoyl)alkyl]carbamoyl]alkoxy, [N-[di(alkoxycarbonyl)alkyl]carbamoyl]alkoxy, [N-[(dicarbamoyl)alkyl]amido, [N-[di(alkoxycarbonyl)alkyl]amido, [N-[(carbamoyl)alkyl]amido, [N-[(alkoxycarbonyl)alkyl]amido, SO3xe2x88x92, aminosulfonyl, (sulfonato)alkyl, (sulfonato)alkoxy, N-[(sulfonato)alkyl]amido, maleimido-, succinimido and [(tri-alkyl)ammonium]-alkoxy groups, wherein the terms alkyl and alkoxy, define groups having 1 to 6 carbons, and alkenyl defines groups having 2 to 5 carbons, and heteroaryl has 1 to 3 heteroatoms independently selected from N, O, and S.
Even more preferably the R21 group is unsubstituted (R17 is H) or the substituent of the R21 group is selected from Cl, Br, F, methyl, methoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, ethoxycarbonyl, (methoxycarbonyl) methoxy, carbamoyl, guanidinyl, ureido, 2-carbamoyl vinyl, 2-(N,N-dimethylcarbamoyl)vinyl, (carbamoyl)methoxy, [N-(pyridyl)carbamoyl]methoxy, morpholinyl, (morpholin-4-yl)alkoxy, [(morpholin-4-yl)alkoxy]alkoxy, 2-(dimethylamino)ethoxy, [N-[(carbamoyl)methyl]carbamoyl]methoxy, (N-(1,3-dicarbamoyl-propyl)carbamoyl)methoxy, (dimethylamino)methyl, SO3xe2x88x92, aminosulfonyl, sodium(sufonato)alkoxy having 2 to 4 carbons, (trimethylammonium) alkoxy having 2 to 4 carbons, poly(alkoxy),, wherein the alkoxy groups have 1 to 3 carbons and n is an integer having the values of 2 to 5, and xe2x80x94(OCH2CH2)nxe2x80x2xe2x80x94Oxe2x80x94 where nxe2x80x2 is 4 or 5. Still more preferably there are one or two R17 substituents (other than hydrogen) in the phenyl (R21) moiety, and preferably the R17 substituent is in a position para (1,4) and/or meta (1,3) to the sulfonyl (SO2) group.
The most preferred compounds of the invention are those wherein the proton pump inhibitor portion is the same as in the widely used proton pump inhibitor drugs known under the names LANSOPRAZOLE, OMEPRAZOLE, PANTOPRAZOLE and RABEPRAZOLE and wherein the R15 group is a benzenesulfonyl group or pyridyl group substituted in the 4 (para) and/or in the 3 (meta) position with a Cl, Br, F, CH3, CH3O, CF3, CF3Oxe2x80x94, (CH3)2N, NH2CO, NH2CONH, NH2C(xe2x95x90NH)NH, 4-morpholino, 2-(4-morpholinyl)ethoxy, 2-[2-(4-morpholinyl)ethoxy]ethoxy, 3-(4-morpholinyl)propoxy, poly(alkoxy)n-alkoxy where n is an integer having the value of 1 to 3, xe2x88x92O3Sxe2x80x94, Na+xe2x88x92O3Sxe2x80x94CH2CH2CH2xe2x80x94O, Xxe2x88x92 (CH3)3NCH2CH2Oxe2x80x94 (X is an anion, such as a halogen ion), NH2COCH2O, (pyridyl)NHCOCH2O, NH2COCH2NH2COCH2O, (CH3)2NCH2 or EtOCO group. These compounds are shown by Formulas 2, 3, 4 and 5, respectively, where R17* represents said Cl, Br, F, CH3, CH3O, CF3, CF3Oxe2x80x94, (CH3)2N, NH2CO, NH2CONH, NH2C(xe2x95x90NH)NH, 4-morpholino, 2-(4-morpholinyl)ethoxy, 2-[2-(4-morpholinyl)ethoxy]ethoxy, 3-(4-morpholinyl)propoxy, poly(alkoxy)n-alkoxy where n is an integer having the value of 1 to 3, xe2x88x92O3Sxe2x80x94, NH2COCH2O, (pyridyl)NHCOCH2O, NH2COCH2NHCOCH2O, (CH3)2NCH2, Na+ xe2x88x92O3Sxe2x80x94 CH2CH2CH2xe2x80x94O, (CH3)3N+CH2CH2Oxe2x80x94, MeOCOCH2CH(COOMe)NHCO or EtOCO groups in the 4 (para) or in the 3 (meta) position of the phenyl ring, or in the 3 and 4 positions of the phenyl ring and where the numbering of the benzimidazole ring is shown in the formulas. In Formula 3 the CH3Oxe2x80x94 group can occupy the 5 or the 6 position of the benzimidazole moiety, and in Formula 4 the CF2HOxe2x80x94 group can occupy the 5 or the 6 position of the benzimidazole moiety. 
The compounds of the invention include
2-[[(3-chloro-4-morpholino-2-pyridyl)methyl]sulfinyl]-5-methoxy-(1H)-benzimidazole,
2-[[[4-(2,2,3,3,4,4,4-heptafluorobutyl)oxy]-2-pyridyl]methyl]sulfinyl]-1H-thieno[3,4-d]imidazole,
2-[[(4-ethythio-3-methyl-2-pyridyl)methyl]sulfinyl]-1h-benzimidazole
2-[(3-methoxyphenyl)methylsulfinyl]-1H-benzimidazole,
2-[(3-methoxyphenyl)methylsulfinyl]imidazolo[5,4-c]pyridine,
2-[(3-methoxyphenyl)methylsulfinyl]imidazolo[4,5-c]pyridine,
and 2-[(3-methoxyphenyl)methylsulfinyl]-5-nitro-benzimidazole, of which 1-position have R15 group. R15 group of these compounds is a benzenesulfonyl group mono-substituted either in the 4 (para) or in the 3 (meta) position with a Cl, Br, F, CH3, CH3O, CF3, CF3O, (CH3)2N, NH2CO, NH2CONH, NH2C(xe2x95x90NH)NH, 4-morpholino, 2-(4-morpholinyl)ethoxy, 2-[2-(4-morpholinyl)ethoxy]ethoxy, 3-(4-morpholinyl)propoxy, NH2COCH2O, (pyridyl)NHCOCH2O, NH2COCH2NH2COCH2O, (CH3)2NCH2, Na+ xe2x88x92O3Sxe2x80x94CH2CH2CH2xe2x80x94O, (CH3)3N+CH2CH2Oxe2x80x94, or EtOCO group.
Examples of the presently most preferred compounds of the invention are as follows:
1-benzenesulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-chlorobenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-chlorobenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-chlorobenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-chlorobenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-chlorobenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-bromobenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-bromobenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-bromobenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-bromobenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-bromobenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-fluorobenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-fluorobenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-fluorobenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-fluorobenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-fluorobenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methylbenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methylbenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methylbenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methylbenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methylbenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methoxybenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methoxybenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methoxybenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methoxybenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-methoxybenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(3-trifluoromethylbenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(3-trifluoromethylbenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(3-trifluoromethylbenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(3-trifluoromethylbenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(3 -trifluoromethylbenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-trifluoromethoxybenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-trifluoromethoxybenzenesulfonyl)-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-trifluoromethoxybenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-trifluoromethoxybenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-trifluoromethoxybenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-dimethylaminobenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-dimethylaminobenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-dimethylaminobenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-ethoxycarbonylbenzenesulfonyl)-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(p-ethoxycarbonylbenzenesulfonyl)-2-[(3-methyl-4-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-(pyridine-3-sulfonyl)-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(pyridine-3-sulfonyl)-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(pyridine-3-sulfonyl)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-(pyridine-3-sulfonyl)-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(pyridine-3-sulfonyl)-6-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[4-[(morpholin-4-yl)phenyl]sulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[4-[(morpholin-4-yl)phenyl]sulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
N-[4-[[5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]benzimidazol-1-yl]sulfonyl]phenyl]urea,
N-[4-[[6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]benzimidazol-1-yl]sulfonyl]phenyl]urea,
N-(4-{[2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenyl)urea,
N-(4-{[2-({[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenyl)urea,
N-(4-{[2-{[(3,4-di(methoxy)-2-pyridyl)methyl]sulfinyl}-5-(difluoromethoxy)-benzimidazol-1-yl]sulfonyl}phenyl)urea,
N-(4-{[2-{[(3,4-di(methoxy)-2-pyridyl)methyl]sulfinyl}-6-(difluoromethoxy)-benzimidazol-1-yl]sulfonyl}phenyl)urea,
2-[4-(3-Methoxy-propoxy)-3-methyl-pyridin-2-ylmethanesulfinyl]-1-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14,17-pentaoxa-benzocyclopentadecene-2-sulfonyl)-1H-benzimidazole,
2-[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-1-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14,17-pentaoxa-benzocyclopentadecene-2-sulfonyl)-1H-benzimidazole,
5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethanesulfinyl)-1-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14,17-pentaoxa-benzocyclopentadecene-2-sulfonyl)-1H-benzimidazole,
6-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethanesulfinyl)-1-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14,17-pentaoxa-benzocyclopentadecene-2-sulfonyl)-1H-benzimidazole,
5-Difluoromethoxy-2-(3,4-dimethoxy-pyridin-2-ylmethanesulfinyl)-1-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14,17-pentaoxa-benzocyclopentadecene-2-sulfonyl)-1H-benzimidazole,
6-Difluoromethoxy-2-(3,4-dimethoxy-pyridin-2-ylmethanesulfinyl)-1-(6,7,9,10,12,13,15,16-octahydro-5,8,11,14,17-pentaoxa-benzocyclopentadecene-2-sulfonyl)-1H-benzimidazole,
2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide,
N-(carbamoylmethyl)-2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide,
N-(carbamoylmethyl)-2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-(4-{[2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenoxy)acetamide,
2-(4-{[2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenoxy)-N-(2-pyridyl)acetamide,
N-(carbamoylmethyl)-2-(4-{[2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenoxy)acetamide,
2-{4-[(5-(difluoromethoxy)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-{4-[(5-(difluoromethoxy)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide,
6N-(carbamoylmethyl)-2-{4-[(5-(difluoromethoxy)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-{4-[(6-(difluoromethoxy)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-{4-[(6-(difluoromethoxy)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide,
N-(carbamoylmethyl)-2-{4-[(6-(difluoromethoxy)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide,
2-(4-{[2-({[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenoxy)acetamide,
2-(4-{[2-({[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenoxy)-N-(2-pyridyl)acetamide,
N-(carbamoylmethyl)-2-(4-{[2-({[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}phenoxy)acetamide,
1-[[4-{3-(morpholin-4-yl)propoxy}phenyl)sulfonyl]-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[4-{3-(morpholin-4-yl)propoxy}phenyl]sulfonyl]-6-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[4-{3-(morpholin-4-yl) propoxy}phenyl]sulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[4-{3-(morpholin-4-yl) propoxy}phenyl]sulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[4-{3-(morpholin-4-yl)propoxy}phenyl]sulfonyl]-2-[(3-methyl-4-methoxypropoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-[[4-{3-(morpholin-4-yl) propoxy}phenyl]sulfonyl]-2-[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-2-[[[(4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]]-1H-benzimidazole,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-6-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]]-1H-benzimidazole,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-[{(N,N-dimethylamino)methyl}benzene-4-sulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[2-acetamido-4-methyl-5-thiazolylsulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(thiophene-2-sulfonyl)-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[{(N,N-dimethylamino)methyl}benzene-4-sulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[2-acetamido-4-methyl-5-thiazolylsulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(thiophene-2-sulfonyl)-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(thiophene-2-sulfonyl)-2-[[[(4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-(thiophene-2-sulfonyl)-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(thiophene-2-sulfonyl)-6-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(thiophene-2-sulfonyl)-]-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-(phenylmethylsulfonyl)-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[(N,N-dimethylamino)benzene-4-sulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(phenylmethylsulfonyl)-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[(N,N-dimethylamino)benzene-4-sulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(pyridine-3-sulfonyl)-2-[[(3-methyl-4-methoxypropoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[4-(morpholin-4-yl)phenylsulfonyl]-2-[[[(4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-2-[[(3-chloro-4-morpholino-2-pyridyl)methyl]sulfinyl]-5-methoxy-(1H)-benzimidazole,
1-benzenesulfonyl-2-[[[(4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-2-[(3-methoxyphenyl)methylsulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-2-[(3-methoxyphenyl)methylsulfinyl]imidazolo[5,4-c]pyridine,
1-benzenesulfonyl-2-[(3-methoxyphenyl)methylsulfinyl]imidazolo[4,5-c]pyridine,
1-benzenesulfonyl-2-[(3-methoxyphenyl)methylsulfinyl]-5-nitro-benzimidazole,
1-benzenesulfonyl-2-[{2-(dimethylamino)phenyl}methylsulfinyl]-1H-benzimidazole,
1-benzenesulfonyl-2-[[[4-(2,2,3,3,4,4,4-heptafluorobutyl)oxy]-2-pyridyl]methyl]sulfinyl]-1H-thieno[3,4-d]imidazole,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-2-[(3-methoxyphenyl)methylsulfinyl]imidazolo{5,4-c]pyridine,
1-[4-[2-(morpholin-4-yl)ethoxy]phenylsulfonyl]-2-[{2-(dimethylamino)phenyl}methylsulfinyl]-1H-benzimidazole,
1-[[2-{2-(morpholin-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[2-{2-(morpholin-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[2-{2-(morpholin-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-2-[[[(4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-[[2-{2-(morpholin-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[2-{2-(morpholin-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-6-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[[2-{2-(morpholin-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole,
1-(4-acetaminobenzenesulfonyl)-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-(4-acetaminobenzenesulfonyl)-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,
1-[(2-dimethylcarbamoyl-vinyl)benzene-4-sulfonyl]-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
-[(2-dimethylcarbamoyl-vinyl)benzene-4-sulfonyl]-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-[(2-carbamoyl-vinyl)benzene-4-sulfonyl]-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-[(2-carbamoyl-vinyl)benzene-4-sulfonyl]-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
sodium 2-[5-methoxy-2-(4-methoxy-3,5-dimethyl pyridin-2-yl
methanesulfinyl)benzimidazole-1-sulfonyl]benzene sulfonate,
sodium 2-[6-methoxy-2-(4-methoxy-3,5-dimethyl pyridin-2-yl
methanesulfinyl)benzimidazole-1-sulfonyl]benzene sulfonate,
{4-[5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinyl)methanesulfinyl benzimidazole-1-sulfonyl]phenoxy}acetic acid methyl ester,
{4-[6-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinyl)methanesulfinyl benzimidazole-1-sulfonyl]phenoxy}acetic acid methyl ester,
1-[(4-(2-dimethylaminoethoxy))benzenesulfonyl]-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
1-[(4-(2-dimethylamino ethoxy))benzenesulfonyl]-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,
N-(2-{4-[5-methoxy-2-(4-methoxy-3,5-dimethyl pyridin-2-yl methanesulfinyl)benzimidazole-1-sulfonyl]-phenoxy}ethyl)-N,N,N-trimethyl ammonium trifluoromethanesulfonate,
N-(2-{4-[6-methoxy-2-(4-methoxy-3,5-dimethyl pyridin-2-yl methanesulfinyl)benzimidazole-1-sulfonyl]-phenoxy}ethyl)-N,N,N-trimethyl ammonium trifluoromethanesulfonate,.
2-{2-carbamoylmethoxy-4-[5-methoxy-2-((4-methoxy-3,5-dimethyl pyridin-2yl)methanesulfinyl)benzimidazole-1-sulfonyl]phenoxy}acetamide,
2-{2-carbamoylmethoxy-4-[6-methoxy-2-((4-methoxy-3,5-dimethyl pyridin-2-yl)methanesulfinyl)benzimidazole-1-sulfonyl]phenoxy}acetamide,
1,3-bis[5-methoxy-2-[((4-methoxy-3,5-dimethyl) pyridin-2-yl) methanesulfinyl]benzimidazole-1-sulfonyl]-benzene,
1,3-bis[6-methoxy-2-[((4-methoxy-3,5-dimethyl) pyridin-2-yl) methanesulfinyl]benzimidazole-1-sulfonyl]-benzene,
1-[5- methoxy-2-[((4-methoxy-3,5-dimethyl) pyridin-2-yl) methanesulfinyl]benzimidazole-1-sulfonyl]-3-[6-methoxy-2-[((4-methoxy-3,5-dimethyl) pyridin-2-yl) methanesulfinyl]benzimidazole-1-sulfonyl]-benzene,
1-[6-methoxy-2-[((4-methoxy-3,5-dimethyl) pyridin-2-yl) methanesulfinyl]benzimidazole-1-sulfonyl]-3-[5-methoxy-2-[((4-methoxy-3,5-dimethyl) pyridin-2-yl) methanesulfinyl]benzimidazole-1-sulfonyl]-benzene, sodium 2-[2-[[(4-methoxypropoxy-3-methyl) pyridin-2-yl]methanesulfinyl]benzimidazole-1-sulfonyl]benzenesulfonate,
2-(2-carbamoylmethoxy-4-{2-[4-(3-methoxypropoxy)-3-methyl pyridin-2-yl methylsulfinyl]benzimidazole-1-sulfonyl}phenoxy)acetamide,
2-{2-carbamoylmethoxy-4-[6-difluoromethoxy-2-(3,4-dimethoxy-pyridin-2-ylmethanesulfinyl)-benzimidazole-1-sulfonyl]-phenoxy}-acetamide,
2-{2-carbamoylmethoxy-4-[5-difluoromethoxy-2-(3,4-dimethoxy-pyridin-2-ylmethanesulfinyl)-benzimidazole-1-sulfonyl]-phenoxy}-acetamide,
2-(2-carbamoylmethoxy-4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl)-benzimidazole-1-sulfonyl}-phenoxy)-acetamide, and
2-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzoimidazole-1-sulfonyl}-benzenesulfonic acid sodium salt.
The compounds of the invention can be prepared by the reacting the 2-pyridylmethylsulfinyl-1H-benzimidazole derivatives (or structurally related compounds) having a free NH group within the imidazole moiety, with an arylsulfonyl chloride. In the broad sense the benzimidazole or structurally related compound which is the starting material having the free NH group, can be described by Formula 1 wherein the R15 group would be H. Similarly, in the broad sense the arylsulfonyl chloride reagent is described by the formula R21(R17)SO2Cl where the R21 and R17 groups are defined as in connection with Formula 1. Reaction Scheme 1 discloses a process for preparing examplary preferred compounds of the invention by reacting the 2-pyridylmethylsulfinyl-1H-benzimidazole derivative of Formula 6 with a benzenesulfonyl chloride derivative of Formula 7 in the presence of a suitable base. The reaction is typically conducted in an inert organic solvent, such as dichloromethane in the presence of an organic base, such as triethylamine. For compounds of Formula 6 and Formula 7 the R1-R3, R6-R9 and R17 groups are defined as in connection with Formula 1. As it can be seen in Reaction Scheme 1, the benzenesulphonylation reaction may give rise to two isomeric or tautomeric products depending on the nature and positions of the R6-R9 substituents on the benzimidazole ring. The two isomeric products (which may be merely tautomers) are shown in Formulas 8 and 9.
The benzenesulfonyl chloride derivatives of Formula 7 can be obtained in accordance with procedures well known in the art.
Those skilled in the art will recognize the 2-pyridylmethylsulfinyl-1H-benzimidazole derivatives of Formula 6 as the proton pump inhibitors generally known in the art and described for example in U.S. Pat. No. 4,686,230 (Rainer et. al.) and in published international application WO 97/48380 (Astra Aktiobiolag). Starting materials within the scope of Formula 13 include the known drugs LANSOPRAZOLE (U.S. Pat. No. 4,628,098), OMEPRAZOLE (U.S. Pat. Nos. 4,255,431 and 4,255,431), PANTOPRAZOLE (U.S. Pat. No. 4,758,579) and RABEPRAZOLE (U.S. Pat. No.5,045,552) Thus, the starting-compounds of Formula 6 can be prepared in accordance with the state-of-the-art, for example as described in U.S. Pat. Nos. 4,686,230, 4,628,098, 4,255,431, 4,758,579, 5,045,552, international application WO 97/48380, Journal of Medicinal Chemistry, 32, 1970-1977 (1989), Chem. Pharm. Bull. 38, 2853-2858 (1990), J. Med. Chem., 34, 1049-1062 (1991), Journal of Medicinal Chemistry, 35, 1049-1057 (1992), and Journal of Medicinal Chemistry, 35, 438-450 (1992), all of which are specifically incorporated herein by reference. 
Instead of using the free benzimidazole compounds of Formula 6, their suitable salts such as the sodium, potassium, magnesium (and other) salts can be reacted with the benzenesulfonyl chloride derivative of Formula 7, to also provide the exemplary compounds of the invention in accordance with Formulas 8 and 9.
Reaction Scheme 2 discloses an alternative method for preparing the exemplary compounds of the invention, shown in Formulas 8 and 9. This reaction involves the oxidation of the corresponding 1-(N)-benzenesulfonyl-benzimidazolyl, 2-pyridylmethyl sulfide compounds of Formulas 10 and 11 to the corresponding sulfoxides. Those skilled in the art will recognize that Formulas 10 and 11 represent isomeric compounds which may be different or identical (tautomeric) with one another depending on the nature and position of the R6-R9 substituents. The oxidation reaction can be performed with oxidizing agents known in the art for forming sulfoxides, for example hydrogen peroxide, m-chloroperoxybenzoic acid and iodosobenzene may serve for this purpose. The oxidation reaction is normally conducted in an aprotic neutral solvent, such as dichloromethane. The sulfide compounds of Formulas 10 and 11 can be obtained by performing a benzenesulphonylation reaction (in analogy to the reaction of Scheme 1) on the sulfide compounds having a free benzimidazole NH group, or their suitable salt. The latter sulfides having the free benzimidazole NH group can be obtained in accordance with the state-of-the-art. 
A significant advantage of the compounds of the present invention is that they can release the active forms of the proton pump inhibitors spontaneously by hydrolysis in the mammalian (including human) body. Hydrolysis can occur chemically or enzymatically. Because the compounds of this invention spontaneously release the active form of the proton pump inhibitor drugs by in vivo hydrolysis, they can attain longer duration of effective drug concentration in the body. Thus, the compounds of the present invention are prodrugs which are converted to active drugs by hydrolysis in the body, providing long duration of effective concentration. The long duration of inhibitory activity by spontaneous hydrolysis of the compounds of this invention allows more effective inhibition of gastric acid secretion, which enables better therapy of acid related disease as defined on pages 1 and 2. Compounds of this invention can be administered for inhibiting gastric acid secretion orally. The typical daily dose of the compounds will depend on various factors such as the individual requirement of each patient. In general, oral and parenteral dosages will be in the range of 5 to 100 mg per day.
Those skilled in the art will readily understand that for oral administration the compounds of the invention are admixed with pharmaceutically acceptable excipients which per se are well known in the art. Specifically, a drug to be administered systemically, it may be confected as a powder, pill, tablet or the like or as a syrup or elixir suitable for oral administration. Description of the subtances normally used to prepare tablets, powders, pills, syrups and elixirs can be found in several books and treatise well known in the art, for example in Remington""s Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pa.
Compounds of the present invention can be combined with certain amounts of known proton pump inhibitors, e. g. LANSOPRAZOLE, OMEPRAZOLE, PANTOPRAZOLE, or RABEPRAZOLE, to provide a drug-prodrug combination, and the combination administered for inhibition of gastric acid secretion. Thus, initially the proton pump inhibitor (drug) inhibits gastric acid secretion of the patient. The aforesaid known and widely used proton pump inhibitors have 60-90 minutes of plasma half-life. As the effective concentration of the proton pump inhibitor (drug) is decreased by metabolism, the compound of the present invention (prodrug) continuosly undergoes hydrolysis and provides and maintains new active inhibitor concentration in the mammalian, including human body.
A disadvantage of the presently used proton pump inhibitors is that for therapy by injection in a liquid form they must be reconstituted from a lyophilized powder in a medium having the high pH of approximately 9.5. The prodrugs of the present invention overcome the disadvantage of requiring a reconstituting medium having such high pH, because the compounds of the present invention can be reconstituted to form an injectable liquid in a medium of approximately pH 6.0 to 8.5. It will be readily appreciated by those skilled in the art that for administration in liquid form by injection the liquid that reconstitutes the drug is a pharmaceutically acceptable aqueous solution that per se is known in the art. Such pharmaceutically acceptable solutions utilized for administration of drugs in injectable form are described for example in the treatise PHARMACEUTICAL DOSAGE FORMS (Parenteral Medications, Volume 1, Edited by K. E. Avis, H. A. Lieberman and L. Lachman (1992).
For example, an exemplary compound of the invention, such as 2-(2-carbamoylmethoxy-4-{2-[4-(3-methoxypropoxy)-3-methyl pyridin-2-yl methylsulfinyl]benzimidazole-1-sulfonyl}phenoxy)acetamide is dissolved in aqueous 40% 2-hydroxypropyl-beta-cyclodextrin solution buffered at pH 7.4, to provide a concentration of 8 mg per ml of the compound of the invention, The latter formulation is injectable intravenously at pH 7.4 and 2-hydroxypropyl-beta-cyclodextrin is known to be safe and non-toxic excreted unchanged in urine within 12 hours. If necessary to dissolve a compound of the invention 20% sulfobutyl ether-beta-cyclodextrin and 20% hydroxypropyl-beta-cyclodextrin can be used for increasing solubility, as suggested (for other drugs) by the publications (J. Clin. Pharm., 1998, 38 (7) 593-602, J. Pharm. Sci., 1997, 86(3) 335-339, J. Pharm. Sci., 1992, 81, 524-548, J. Pharm. Sci., 1999, 88, 1016-1020, and J. Pharm. Sci., 1999, 88, 1107-1111.).
Among the benefits of the pre-proton pump inhibitor (P-PPI) type of drugs of the present invention is their ability to provide more effective treatment of erosive esophagitis and of less severe reflux diseases as well. This is because effective treatment of erosive esophagitis (and to a lesser extent of lesser reflux diseases) requires prevention of the reflux of gastric contents at pH 3.0 or still lower pH. The current PPI drugs allow several acidic excursions to pH  less than 2.0 per day, resulting in a moderate to weak amelioration of symptoms. However, healing would require elevation to pH  greater than 4.0 for about 16 hours per day or longer. When, as in current usual treatment by PPIs, the other 8 hours contain episodic acidity to pH 3.0 or less, the patients tend to continue to complain of pain. The more effective and more continues acid suppression by the drugs of the present invention is likely to result in substantially better treatment of this disease, as well as faster healing of all acid related erosions or ulcers.
The pre-proton pump inhibitor (P-PPI) type of drugs of the present invention provide improved dual therapy for H. pylori eradication. This is because the PPI""s synergize with cell division dependent antibiotics such as amoxicillin (cell wall biosynthesis) and clarithromycin (protein synthesis) by elevating gastric surface pH to enable a larger fraction of the bacterial population to be in dividing phase during presentation of the antibiotic to the gastric lumen. However, their effect on intragastric pH is limited by their dwell time in the plasma. The pre-proton pump inhibitor (P-PPI) type of drugs of the present invention can continuously elevate intra gastric pH close to neutrality on current once a day therapy. Therefore, 100% eradication of the bacteria is expected in dual therapy with the prodrugs of the invention (for example a pro-drug of OMEPRAZOLE in accordance with the invention) plus an effective antibiotic, such as amoxicillin.
Even monotherapy for H. pylori eradication is likely to be successful with the pre-proton pump inhibitor (P-PPI) type of drugs of the present invention. This is because in the absence of acid, the enzyme H. pylori urease elevates environmental pH to  greater than 8.3, which is toxic to the organism. PPI""s in current formulation inhibit growth or present of the organism in the antrum, due to elevation of antral pH to close to neutrality. Elevation of 24 hour pH to neutrality, as it can be accomplished with the drugs of the present invention, is likely to result in xe2x80x9cself eradicationxe2x80x9d of the bacteria.
Approximately 30% of patients with gastrointestinal distress appear with symptoms without quantitative underlying disease (non-ulcer dyspepsia). The most likely cause for these symptoms is upper gastrointestinal afferent nerve sensitivity to gastric acid. Only acid ablation ameliorates these symptoms and this can be attained with the drugs of the present invention.
By way of concrete examples, the following tests and results are described. Certain compounds of the invention have been tested in one or more standard laboratory tests that demonstrate gastric antisecretory activity. The compounds of the invention did not directly inhibit the K+-dependent ATP hydrolysis of gastric H,K-ATPase. However, after hydrolysis the compounds of this invention showed strong inhibition of gastric H,K-ATPase activity. This is consistent with the knowledge that the compounds obtained by hydrolysis e. g. LANSOPRAZOLE, OMEPRAZOLE, PANTOPRAZOLE and RABEPRAZOLE are well known H,K-ATPase inhibitors. For example, 1-benzenesulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole was tested for inhibitory activity of gastric H,K-ATPase. Initially this compound did not inhibit gastric H,K-ATPase. However, gastric H,K-ATPase activity was spontaneously inhibited as hydrolysis of this compound in aqueous solution at pH 7.4 proceeded. After 5.75 hr -hydrolysis at pH 7.4, this compound inhibited 91% of gastric H,K-ATPase activity, same as 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (OMEPRAZOLE) which was the product of the hydrolysis. It was determined that 1-benzenesulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-H-benzimidazole was hydrolyzed to 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (OMEPRAZOLE) with a half-life (txc2xd) 3xc2x10.5 hr at 37xc2x0 C. at pH 7.4 in the presence of the plasma proteins. Another good example is 2-(2-carbamoylmethoxy-4-{2-[4-(3-methoxypropoxy)-3-methyl pyridin-2-yl methylsulfinyl]benzimidazole-1-sulfonyl}phenoxy)acetamide. The half life of this compound dependes on pH. At pH 2 the half-life of this compound is about 1.8 hr (which mimics in vivo gastric juice pH), at pH 7.4 in the presence of bovine serum albumin it is about 3.7 hr (which mimics blood plasma serum), at pH 8 it is about 10.7 hr (which mimics similar pH of duodenum), and at pH 7.4 without bovine serum albumin it is about 22.2 hr. This data show that this pro-drug compound of the invention is reasonably stable in the stomach compared to the parent RABEPRAZOLE, which has a half-life of a few minutes at pH 2. Based on these measured characteristics the compound 2-(2-carbamoylmethoxy-4-{2-[4-(3-methoxypropoxy)-3-methyl pyridin-2-yl methylsulfinyl]benzimidazole-1-sulfonyl}phenoxy)acetamide is expected to be well absorbed, and slowly release the parent RABEPRAZOLE in the blood, resulting in long-lasting in vivo activity. This compound can also be administered intravenously in an aqueous solution at pH 7.4 which solution may include 2-hydroxypropyl-xcex2-cyclodextrin.
When a mixture of 2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide and 2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide was orally administrated to male rat, 5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (OMEPRAZOLE) was continuously released to the plasma for more than 4 hours as a result of the hydrolysis of 2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl }benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide and 2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide. As a control experiment, when OMEPRAZOLE was administrated to male rat, OMEPRAZOLE has completely disappeared from the plasma within 1.5 hr. Bioavailability of2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide was much higher than that of OMEPRAZOLE after oral administration.
Additional experiments, described below, with further compounds of the invention showed good inhibition of gastric acid secretion. For example, when a mixture of 2-{2-carbamoylmethoxy-4-[5-methoxy-2-((4-methoxy-3,5-dimethyl pyridin-2-yl)methanesulfinyl)benzimidazole-1-sulfonyl]phenoxy}acetamide and 2-{2-carbamoylmethoxy-4-[6-methoxy-2-((4-methoxy-3,5-dimethyl pyridin-2-yl)methanesulfinyl)benzimidazole-1-sulfonyl]phenoxy}acetamide (1:1 mixture of isomers) was administrated to male rat, gastric acid secretion was observed to be significantly and continuously inhibited. Using pylorus-ligated male rats, when acid-output stimulated by histamine was measured, intraduodenal administration of 10 xcexcmole of 2-{2-carbamoylmethoxy-4-[5-methoxy-2-((4-methoxy-3,5-dimethyl pyridin-2-yl)methanesulfinyl)benzimidazole-1-sulfonyl]phenoxy}acetamide and 2-{2-carbamoylmethoxy-4-[6-methoxy-2-((4-methoxy-3,5-dimethyl pyridin-2-yl)methanesulfinyl)benzimidazole-1-sulfonyl]phenoxy}acetamide (1:1 mixture of isomers) provided 64.2% inhibition, while OMEPRAZOLE provided only 54.6% under identical condition. Also, when acid-output stimulated by histamine and carbachol was measured after 5.5 hr of oral administration, the latter mixture of isomers provided 49.7% inhibition, while OMEPRAZOLE provided only 19.6% inhibition. Under similar condition, (pyridine-3-sulfonyl)OMEPRAZOLE (the compound of Example 25) inhibited 61% and a mixture of 2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl } benzimidazol-1-yl)sulfonyl]phenoxy} acetamide and 2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl} benzimidazol-1-yl)sulfonyl]phenoxy}acetamide inhibited 65%, while OMEPRAZOLE showed relatively rapid decline of inhibition (about 20%) with fast elimination of drug in the plasma level. Similarly, 2-(2-carbamoylmethoxy-4-{2-[4-(3-methoxypropoxy)-3-methyl pyridin-2-yl methylsulfinyl]benzimidazole-1-sulfonyl}phenoxy)acetamide provided 56% inhibition after 5 hr of oral administration, while the parent RABEPRAZOLE showed 32% of inhibition under the same condition. 2-(4-{[2-({[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl) benzimidazol-1-yl]sulfonyl}phenoxy)acetamide provided 46.9% inhibition and 2-(2-carbamoylmethoxy-4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl methanesulfinyl]-benzimidazole-1-sulfonyl}-phenoxy)-acetamide gave 36.8% inhibition, while the parent LANSOPRAZOLE showed only 29% inhibition after 4 hour of oral administration.
It is well known that oral potency of OMEPRAZOLE without enteric-coating is significantly lower than that found after i.v. or i.d. administration in both rat and dog (Larsson et al., Scand. J. Gastroenterology, vol. 20 (suppl. 108), 23-35, 1985). The compounds of this invention do not need enteric-coating for protection from acid-catalyzed decomposition. Furthermore, the compounds of this invention provide continuous inhibition of gastric acid secretion, as described above.